ES2761333T3 - Pharmaceutical compositions containing Pediococcus and methods to reduce the symptoms of gastroenterological syndromes - Google Patents

Abstract

A pharmaceutically acceptable composition comprising approximately the following amounts of ingredients per serving or dose, where CFU means a Colony Forming Unit: Pediococcus acidilactici 1.5 billion CFU Bifidobacterium brief 0.5 billion CFU Bifidobacterium infantis 0.5 thousand million CFU Lactobacillus paracasei 0.5 billion CFU Lactobacillus salivarius 0.5 billion CFU Bifidobacterium lactis 1.0 billion CFU Bifidobacteriurn longum 1.0 billion CFU Streptococcus thermophilus 1.0 billion CFU Lactobacillus bulgaricus 1.0 billion CFU Lactobacillus casei 2.5 billion CFU Lactobacillus plantarum 2.5 billion CFU Lactobacillus acidophilus 3.0 billion CFU Bifidobacterium bifidum 3.5 billion CFU Lactobacillus rhamnosus 6.0 billion million CFU for use in a method of improvement and treatment of at least one symptom of irritable bowel syndrome, inflammatory bowel disease, or gastritis in a mammal in need.

Description

DESCRIPTION

Pharmaceutical compositions containing Pediococcus and methods to reduce the symptoms of gastroenterological syndromes

Field of the Invention

The present invention relates, in general, to new probiotic microorganisms and their therapeutic uses. Furthermore, this invention relates to a prophylactic and therapeutic composition comprising the same to contribute in many probiotic ways to the general health of the host and to improve and treat at least one symptom of irritable bowel syndrome, inflammatory bowel disease, or gastritis in a mammal that needs it.

Background of the Invention

Disorders involving abnormal functioning of the gastrointestinal tract afflict large segments of the world population. The most prevalent of functional disorders in the absence of structural abnormalities is irritable bowel syndrome (IBS). The most common inflammatory gastrointestinal diseases are inflammatory bowel disease (IBD, which includes Crohn's disease, ulcerative colitis, and undetermined colitis), and gastritis. These conditions profoundly affect the quality of life of those who suffer them, and incur significant economic costs (Engel & Neurath, 2010; Loftus et al., 2000; Longstreth et al., 2006; Madden &Hunter; Salonen et al., 2010). IBS is estimated to affect 5 million Americans. IBS is characterized by recurring symptoms of abdominal pain, bloating, and impaired bowel function in the absence of structural abnormalities. IBD affects between 2 and 6% of Americans. IBD is characterized by frequent and progressive symptoms of abdominal pain, diarrhea, rectal bleeding, and weight loss. Gastritis is estimated to affect 4.5 million people in the United States. Gastritis involves chronic inflammation of the stomach, leading to pain in the upper abdomen and nausea. Gastritis is also the leading cause of acquired failure of the gastric acid barrier, resulting in the development of gastric and duodenal ulcers and stomach cancer in patients with H. pylori infection.

Today there is evidence that these complex disorders have something in common: an imbalance (dysbiosis) between the protective and harmful gastrointestinal organisms, even though no specific pathogen can be identified (Blaser, 1998; Bullock et al., 2004; Collins et al. al., 2009; Corthesy et al., 2007; Lin, 2004; Ott et al., 2004; Pimental et al., 2011; Salonen, et al., 2010). The role of dysbiosis in these diseases provides the rational basis for the use of agents such as antibiotics, which alter the microbial composition of the GI tract. However, the use of antibiotics has been linked to serious side effects, complications, and bacterial resistance (Engel & Neurath, 2010; Grundmann et al., 2010). Furthermore, antimicrobial therapies provide inferior results compared to antimicrobial therapies for other common infectious diseases (Camilleri & Tack, 2010; Rimbara et al., 2011).

IBS is classified as a functional disorder because there is no sign of disease when the small intestine and colon are examined. IBS is characterized by recurrent symptoms of abdominal pain, bloating, and impaired bowel function in the absence of structural abnormalities (see Brandt et al., 2009; Chang & Talley, 2010; Grundman et al., 2010). According to the Rome II criteria, IBS sufferers can be grouped into three symptomatic subtypes lowered in the form of stool, stool frequency and defecation symptoms: prevalence of diarrhea (IBS-D), prevalence of constipation ((IBS- C), and mixed subtype (IBS-M) with alternating episodes of both diarrhea and constipation.More recently, the Rome III criteria have been published, which focus on the stool form rather than on the frequency of defecation ( Longstreth et al., 2006) The most important physiological aberrations in IBS include visceral hypersensitivity, abnormal bowel motility, and autonomic nervous system dysfunction, the interactions of which are suggested to make bowel function sensitive to numerous exogenous and endogenous factors, such as GI microbiota, diet and psychosocial factors.

The presence of low-level inflammation has also been observed in the GI mucosa of IBS patients. Several studies have examined the fecal flora of IBS patients and have found a decrease in Escherichia coli, lactobacilli, and bifidobacteria and an increase in aerobic microorganisms compared to healthy volunteer individuals (Jonkers & Stockbrugger, 2007; Madden & Hunter, 2002; Salonen et al., 2010).

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that includes Crohn's disease and ulcerative colitis (Longstreth et al., 2006; Engel & Neurath, 2010; Loftus et al., 2000). The causes of IBD are not known, but a main theory suggests that some agent, perhaps a virus or bacteria, alters the body's immune response, triggering an inflammatory reaction in the intestinal wall. Crohn's disease most commonly affects the small intestine and / or colon, while ulcerative colitis affects the large intestine, mainly the sigmoid / rectal region of the large intestine. The diagnosis of IBD is suggested by the symptoms of abdominal pain, rectal bleeding, and diarrhea. The latter diagnosis is based on a combination of history, endoscopic findings, histological features, and negative stool studies for infectious agents (Silverberg et al., 2005). Cases that cannot be diagnosed as ulcerative colitis or Crohn's disease are known as indeterminate colitis. No specific microorganism has yet been described as a possible causative factor in IBD. However, it has observed a change in the bacterial composition of both the faecal microbiota and the mucosa (Ott et al., 2004).

Gastritis involves chronic inflammation of the stomach and duodenum that is typically associated with H. pylori infection. The most common symptoms are pain in the upper abdomen and nausea; other symptoms are indigestion, bloating, nausea, and vomiting. Gastritis can be associated with pernicious anemia. The main acute causes of gastritis are excessive alcohol consumption or prolonged use of non-steroidal anti-inflammatory drugs (also known as NSAIDs), such as aspirin or ibuprofen. Gastritis can develop after major surgery, traumatic injury, burns, serious infections, weight loss surgery that involves girdle application or reconstruction of the digestive tract, chronic bile reflux, stress, and certain autoimmune disorders. Gastroscopy, a blood test, a urea breath test, and / or a stool test can be used to diagnose gastritis (Sepúlveda & Patil, 2010).

Standard treatment for gastritis has been a one-week "triple therapy" consisting of proton pump inhibitors and the antibiotics clarithromycin and amoxicillin, but the emergence of drug resistance has compromised the use of this regimen ( Camilleri & Tack, 2010; Rimbara et al., 2011). Antibiotics ciprofloxacin and metronidazole have been used to treat gastritis, but the side effects of these antibiotics limit their use (Engel & Neurath, 2010; Grundman et al., 2010). A newer antibiotic, rifaximin, may be more effective than previous drugs (Pimental et al., 2010), but it is currently approved only for the treatment of traveler's diarrhea. IBD is usually treated with immunosuppressive agents. Surgery is frequently required. IBS therapy is directly symptom relief and is often unsatisfactory.

Due to studies suggesting that dysbiosis is important in the etiology of these disorders, interest has emerged in the identification of probiotic compositions that are capable of ameliorating and treating symptoms of IBS, IBD, and gastritis and improving the response to conventional treatments. .

Additionally, it is well known that probiotics are described as "live microorganisms that, when administered in adequate amounts, confer a benefit for the health of the host" (reports of the Food and Agriculture Organization of the United Nations and the World Health Organization, Alternative Medicine 2001). Probiotics are widely applied as nutritional supplements in animals and humans. For example, yeast is used as a nutritional supplement for livestock, and yogurt with Lactobacillus and / or Bifidobacterium lactic acid bacteria is commonly used to prevent and treat gastrointestinal (GI) infectious diseases related to diarrhea. Multiple unique properties of probiotics such as anti-infective properties, immunomodulatory effects, enhanced barrier functions, metabolic effects, and alternating intestinal mobility or function make probiotics an effective alternative type medicine for animals and humans.

Although probiotic products such as short chain fatty acids (SCFA), cell wall peptidoglycan, and short-chain DNA fragments containing CpG sequences may have beneficial probiotic effects, the administration of live microorganisms to animals and humans remains the essential application. and the focus of probiotic research studies. To achieve the maximum effects of probiotics in animals and humans, live bacteria that reach the gastrointestinal tract must be administered for multiplication. Lactobacillus spp and Bifidobacterium spp are the two genera of probiotics most commonly described in the scientific literature and in commercial products. Both Lactobacillus spp and Bifidobacterium spp are facultative or strict anaerobic bacteria. Most Lactobacillus and Bifidobacterium species (or strains) are sensitive to exposure to oxygen and elevated temperature. It is difficult to maintain the viability of Lactobacillus and Bifidobacterium at room temperature in consistent opening and closing operations. For this reason, variable results are often described, especially for commercially available products that are required to have long-term storage and transportation at various temperatures.

In sum, there is a high frequency of incomplete or absent response of IBS, IBD and gastritis to current medical therapies. Thus, a need for more effective methods, compositions, etc., which can improve and treat one or more symptoms associated with these diseases, has been unmet. Effective dietary and / or pharmaceutical interventions for these conditions could have a significant impact on public health. The systems and methods, etc., present provide these and / or other advantages.

WO 2011/092261 A1 refers to a composition comprising an effective amount of Lactobacillus CECT 7484, Lactobacillus plantarum CECT 7485 and Pediococcus acidilactici CECT 7483 for the treatment of intestinal inflammation.

US 2011/0038838 A1 includes methods for treating cats and dogs with inflammatory bowel disease.

WO 2005/077391 A1 refers to the use of at least two strains of lactic bacteria selected from the group comprising Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei and Lactobacillus plantarum to prepare a formulation for the prevention or treatment of inflammatory disorders induced by stress.

EP 2277524 A1 refers to the treatment of irritable bowel syndrome and inflammatory bowel disease.

Objects of the invention

Accordingly, it is an object of the present invention to provide probiotic compositions for use in a method of amelioration and treatment of at least one symptom of irritable bowel syndrome, inflammatory bowel disease, or gastritis.

These and other objects of the present invention will become more readily apparent from the following description and examples.

Compendium of the Invention

The present invention provides a pharmaceutically acceptable composition comprising approximately the following amounts of ingredients per serving or dose, where CFU stands for a Colony Forming Unit: Pediococcus acidilactici 1.5 billion CFU

Bifidobacterium brief 0.5 billion CFU

Bifidobacterium infantis 0.5 billion CFU

Lactobacillus paracasei 0.5 billion CFU

Lactobacillus salivarius 0.5 billion CFU

Bifidobacterium lactis 1.0 billion CFU

Bifidobacterium longum 1.0 billion CFU

Streptococcus thermophilus 1.0 billion CFU

Lactobacillus bulgaricus 1.0 billion CFU

Lactobacillus casei 2.5 billion CFU

Lactobacillus plantarum 2.5 billion CFU

Lactobacillus acidophilus 3.0 billion CFU

Bifidobacterium bifidum 3.5 billion CFU

Lactobacillus rhamnosus 6.0 billion CFU

for use in a method of ameliorating and treating at least one symptom of irritable bowel syndrome, inflammatory bowel disease, or gastritis in a mammal in need.

Description of Preferred Embodiments

Diagnosis and pathophysiology

In one aspect, the compositions herein are intended to provide probiotic compositions that are capable of ameliorating and treating one or more signs or symptoms of IBS, IBD, and gastritis in individuals in need. The signs and symptoms of gastritis, which can be reduced by the compositions of the present invention, include a stabbing pain or ailment (indigestion) in the upper abdomen that can become worse or better with food; nausea; threw up; loss of appetite; belching or bloating; a feeling of fullness in the upper abdomen after eating; weight loss, gastric ulcer; duodenal ulcer; inflammation of the inner lining of the stomach; a positive urease test in the stool; a positive urea breath test.

Signs and symptoms of IBS, which can be reduced by the compositions of the present invention include: abdominal pain or cramps; a bloated feeling; gas (flatulence); diarrhea or constipation; a change in the frequency of bowel movements; a change in the appearance of bowel movements; feelings of uncontrollable urge to have a bowel movement; and mucus in the stool.

Signs and symptoms of IBD (Crohn's disease, ulcerative colitis, and undetermined colitis) that can be reduced by the compositions of the present invention include: abdominal pain; fever; loss of appetite; pain with passing stool; diarrhea; unintended weight loss, constipation; rectal bleeding; bloody stools; intestinal inflammation, abscesses and fistulas; and information on the ileal pouch (pouchitis).

To benefit from the compositions herein, individuals do not need to have been diagnosed with a microbial infection.

The compositions can be used as dietary supplements or as food additives or as pharmaceutical agents or otherwise as desired to reduce the symptoms of IBS, IBD and gastritis. The methods of this specification include methods, kits, labels, systems, etc., aimed at labeling, marketing and otherwise providing the compositions to healthcare professionals and / or consumers for use in reducing IBS symptoms. , IBD and gastritis.

The inclusion of at least one strain of Pediococcus in the composition is essential for this invention.

In a further embodiment, the compositions are supplied in capsules or other suitable administration formats, and a single capsule provides a complete service. This specification describes that each capsule comprises at least approximately 1 million and up to 150 billion Colony Forming Units (CFU) of Pediococcus per 1 capsule service and at least approximately 1 million CFU of the additional microorganism per 1 capsule service . Throughput is described in this specification as approximately 150 billion CFU per gram of material. Other yields may also be used if desired.

The Pediococcus strain is one or more of Pediococcus acidilactici, Pediococcus pentosaceus, Pediococcus damnosus, Pediococcus dextrinicus, Pediococcus cerevisiae, or Pediococcus parvulus.

In accordance with the present invention, Pediococcus acidilactici is used .

The selected species of Pediococcus is combined with other probiotics. The additional probiotic can be any microorganism that has a beneficial effect on human health. Typically, the additional probiotic is one or more of: Lactobacillus acidophilus, L. brevis, L. bulgaricus, L. casei, L. crispatus, L. curvatus, L. fermentum, L. gasseri, L. helveticus, L. johnsonii, L. paracasei, L. paraplantarum, L. pentosus, L. plantarum, L. reuteri, L. rhamnosus, L. salivarius, L. sakei, Lactococcus lactis, Leuconostoc lactis, Ln. pseudomesenteroid, Ln. mesenteroids, Bifidobacterium adolescentis, B. animalis, B. bifidum, B. breve, B. lactis, B. longum, B. infantis, Streptococcus thermophilus, Saccharomyces boulardii, Saccharomyces cereviseae, Bacillus subtilis, B. coagulans (frequently mislabeled as Lactobacillus sporogenes), B. licheniformis, B. cereus, Enterococcus faecium, Escherichia coli Nessle 1917, Proprionibacterium acidipropionici, P. freudenreichii, P. jensenii, and P. thoenii.

In a further embodiment, none of the probiotic organisms contained in the composition has been propagated or is propagated or grown in media containing casein or gluten.

In yet another embodiment, the composition such as a dietary supplement is a dried powder, a tablet, or a gelatin capsule. Illustrative methods for encapsulating probiotics can be found, eg. eg, in US Patent Application 2007/0122397 and in the scientific literature.

In a further embodiment, the composition is supplied together with an ingestible support material for human consumption. Illustrative ingestible support materials include a cereal-based product, rice cake, soy cake, food bar product, cold-formed food bar product, custard, pudding, gelatin, rice milk, soy milk, yogurt, kefir, product of fruit puree, caramel, caramel bar, and applesauce. Numerous methods for formulating probiotic-ingestible support materials are known in the literature.

In another embodiment, the product may be a kit or system in which the compositions, capsules, etc., of this specification are contained in a pharmaceutically acceptable container and a description, brochure, information sheet, catalog, or label explaining that the product can reduce one or more symptoms of IBS, IBD or gastritis, and / or that the product is casein and gluten free and / or is hypoallergenic. Additionally, the product may be marketed along with the written description, brochure, information sheet, catalog, or label that explains that the product may reduce one or more symptoms of IBS, IBD, or gastritis / gastric ulcer, and / or that the product is free of casein and gluten.

In a further embodiment, the product is marketed along with a written description, brochure, information sheet, catalog, or label explaining that the product is hypoallergenic.

Ingredients and probiotic compositions

The term "probiotics", within the context of the present invention, is used in accordance with its usual meaning, for example as selected viable microbial dietary supplements that, when introduced in sufficient quantities, beneficially affect the human organism by their effects on the tract gastro-intestinal (Holzapfel et al., 2001; Holzapfel & Schillinger, 2002). FAO / WHO has adopted the definition of probiotics as "live microorganisms that, when administered in adequate amounts, confer a health benefit to the host" (FAO / WHO guidelines, 2002). These beneficial bacteria can be found for example in milk or in milk processing factories, live or rotting plants, and also in the intestines of man and animals.

Currently, the best studied probiotics are lactic acid bacteria, particularly Lactobacillus spp. and Bifidobacterium spp. Lactobacillus is a genus of facultative Gram-positive anaerobic bacteria. The genus Lactobacillus currently comprises more than 100 species and encompasses a wide diversity of organisms. These are common and usually benign. In humans, they are present in the vagina and the gastrointestinal tract, where they are symbiotic and constitute a small portion of the intestinal flora (Tannock, 1999). In humans, studies have been conducted with L. acidophilus, L. salivarius, L. johnsonii, L. casei, L. lactis, L. reuteri, L. plantarurn, L. rhamnosus, L. brevis, L. gasseri, and other species and subspecies. The use of Lactobacillus species in human studies has been extensively reviewed in the scientific literature, including the references provided herein.

Bifidobacterium is a genus of Gram-positive anaerobic bacteria, currently comprising 31 identified species, 11 of which have been detected in human feces (Tannock, 1999). Bifidobacteria are gram-positive, irregular, or branched rod-shaped bacteria commonly found in the intestines of humans and most animals and insects. While B. infantis, B. brevi, and B. longum are the largest group of bacteria in the gut of children, Bifidobacteria are said to be only the 3rd or 4th largest group in adults (and comprise only 3 -6% of the fecal flora of adults). Bifidobacteria inhibit the growth of Candida albicans, E. coli, and other pathogenic bacteria. B. infantis has been shown to dramatically reduce symptoms of irritable bowel syndrome (IBS) (Whorwell et al., 2006).

Lactobacilli and Bifidobacteria have been examined for their efficacy in preventing and treating a diverse spectrum of gastrointestinal disorders. Among other benefits, these organisms are believed to restore and maintain immune system function and gastrointestinal barrier function, and reduce inflammation (Corthésy et al., 2007; Parvez et al., 2006).

The effects of Lactobacillus and Bifidobacterium in humans have been reviewed by Jonkers & Stockbruegger, 2007; Lesbros-Pantoflickova; Moayyedi et al., 2010; Gareau et al., 2010; Parvez et al., 2006; Lesbros-Pantoflickova D, et al.

2007). Midolo et al. (1995) reported that six L. acidophilus strains and one L. casei subsp. rhamnosus inhibited the growth of H. pylori in vitro. The administration of Lactobacíllus and Bifidohacteria improves gastritis; the effect is statistically significant although weak (Lesbros-Pantoflickova D, et al. 2007). A product, known as VSL # 3, has been shown to reduce symptoms of ulcerative colitis and pouchitis (inflammation of the ileal pouch; reviewed by Corthesy et al., 2007). A probiotic / prebiotic mixture known as Synbiotic 2000 had no effect on post-operative recurrence of Crohn's disease (Chermesh, 2007).

Saccharomyces boulardii is a transient yeast probiotic widely used to treat various types of diarrhea. It is a resistant microorganism, both to acids and to temperature, which is not affected by antibiotics. S. boulardii has been reported to have beneficial effects in patients with Crohn's disease, IBS, and gastritis (Guslandi et al., 2000; Choi et al., 2011; Szajewska et al., 2010).

Pediococcus can be described as "the only homofermentative acidophilic lactic acid bacteria that alternately divide in two perpendicular directions to form tetrads" (Simpson and Taguchi, 1995). Phylogenetically, Pediococcus and Lactobacillus form a super-grouping that can be divided into two sub-groupings. All Pediococcus species fall within the Lactobacillus casei - Pediococcus subgroup . Morphologically, pediococci (cocci; 0.6-1.0 mm in diameter) and lactobacilli (rods) are different. Currently, five species belong to the genus Pediococcus : Pediococcus acidilactici, Pediococcus damnosus, Pediococcus dextrinicus, Pediococcus parvulus, and Pediococcus pentosaceus.

P. pentosaceus is used as an acid-producing starter culture in sausage fermentations, cucumber and green bean fermentations, soy milk fermentations, and silage, and is a typical component of the microflora of most cheese varieties. during curing. Pediococcus species have been used as probiotics in the livestock and companion animal industries (US Patent Applications 20060008511 and 20070020328) and are generally recognized as safe for human consumption (GRAS) (Ishibashi & Yamazaki, 2001). A strain of P. acidilactici (LMG P-21927) has been isolated from human faeces (Speelmans et al; US Patent Application 2006/0165661; WO2004 / 110466).

The antimicrobial effects of Pediococcus on foodborne pathogens such as Listeria have been determined. The antibacterial properties of Pediococcus are due to bactericidal peptides known as pediokines, which are of great interest as food bioconservatives. Several studies have been conducted to examine the effects of pediocines on H. pylori. Kim et al. (2003) reported that purified PO2 pediocin had weak activity against H. pylori, but Midolo et al. (1995) found no effect of live Pediococcus on H. Pylori. None of the studies contemplate the use of live Pediococcus for the treatment of gastritis, IBS or IBD in humans.

The inventors have previously described compositions and methods comprising Pediococcus for use in humans (US Published Application No. 2011/0091431). The present invention specifies the use of these compositions and methods to improve and treat at least one symptom of gastritis, IBS and IBD in people who need it.

Although not necessary for an understanding of the compositions herein, the beneficial effects of the present compositions in reducing symptoms of IBS, IBD, and gastritis may result from an effect of Pediococcus as an immunomodulator, which reduces inflammation and improves the host response against the disease. The dosage of Pediococcus is also important for the successful colonization of the gastrointestinal tract. Without being bound by theory, these properties may allow the Pediococcus compositions of this invention to confer or restore more normal neurogastrointestinal and immune function in individuals with IBS, IBD, and gastritis. For this reason, individuals who have been diagnosed with IBS, IBD, or gastritis may benefit from the new compositions.

The compositions considered herein can be administered, for example, as dietary supplements, food and beverage additives, food and beverage ingredients, and pharmaceutical agents. Any suitable route of administration, typically food / oral, can be used.

The compositions set forth herein can include or be used in combination with compositions comprising digestive enzymes. For example, the compositions can be used in combination with a formulated combination of digestive enzymes known as EnzymAid ™ (Kirkman Labs, Oregon) and a wide variety of other formulations. Typically, the digestive enzymes will be administered as a separate tablet or capsule or powder. If desired, a digestive enzyme formulation can be given for a prescribed period of time to a patient prior to initiation of treatment, for example over a period of 1-3 days to 1-4 weeks prior to initiation of treatment with the compositions described in this specification. Examples of digestive enzyme formulations that are suitable for use in the present invention include, but are not limited to, the products of ProThera Inc. and Klaire Labs, Inc. (Reno, Nevada), known as VitalZymes ™ Complete; VitalZymes ™ Forte; VitalZymes ™ Chewables; and SerenAid®, and any of the ingredients contained in them. The compositions described herein can be used after treatment with antibiotic or antifungal agents, or concomitantly with such treatments.

The compositions set forth herein can be used in conjunction with a gluten-free and casein-free diet. Thus, the compositions of the present invention can be used in conjunction with any of the methods and compositions set forth in Houston (US 6,447,772) and / or Wilkinson (US 6,251,391) including the ScrenAid® brand product of ProThera, Inc.

The compositions of this invention preferably consist of the following ingredients (% relative CFU content):

Pediococcus acidilactici 1% to 99%

Pediococcus pentosaceus 1% to 99%

Pediococcus damnosus 1% to 99%

Pediococcus dextrinicus 1% to 99%

Pediococcus parvulus 1% to 99%

Bifidobacterium lactis 1% to 99%

Bifidobacterium animalis 0% to 99%

Bifidobacterium adolescentis 0% to 98%

Bifidobacterium bifidum 0% to 98%

Bifidobacterium brevis 0% to 98%

Bifidobacterium infantis 0% to 98%

Bifidobacterium longum 0% to 98%

Lactobacillus acidophilus 0% to 98%

Lactobacíllus brevis 0% to 98%

Lactobacillus bulgaricus 0% to 98%

Lactobacillus casei 0% to 98%

Lactobacillus crispatus 0% to 98%

Lactobacillus curvatus 0% to 98%

Lactobacillus fermentum 0% to 98%

Lactobacillus gasseri 0% to 98%

Lactobacillus helveticus 0% to 98%

Lactobacillus johnsonii 0% to 98%

Lactobacillus paracasei 0% to 98%

Lactobacillus paraplantarum 0% to 98%

Lactobacillus pentosus 0% to 98%

Lactobacillus plantarum 0% to 98%

Lactobacillus reuteri 0% to 98%

Lactobacillus rhamnosus 0% to 98%

Lactobacillus sakei 0% to 98%

Lactobacillus salivarius 0% to 98%

Lactococcus lactis 0% to 98%

Leuconostoc lactis 0% to 98%

Leuconostoc pseudomesenteroid 0% to 98%

Leuconostoc mesenteroides 0% to 98%

Saccharomyces boulardii 0% to 98%

Saccharomyces cerevisiae 0% to 98%

Streptococcus thermophilus 0% to 98%

Bacillus subtilis 0% to 98%

Bacillus coagulans 0% to 98%

Bacillus licheniformis 0% to 98%

Bacillus cereus 0% to 98%

Enterococcus faecium 0% to 98%

Escherichia coli Nessle 19170 % to 98%

Proprionibacterium acidipropionic 0% to 98%

Proprionibacterium freudenreichii 0% to 98%

Proprionibacterium jensenii 0% to 98%

Proprionibacterium thoenii 0% to 98%

Enterococcus faecium 0% to 98%

The ingredients indicated above may also be present, for example, in intervals of more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%. In accordance with the present invention, the compositions contain the following amounts of ingredients per serving or dose, where CFU stands for a Cologne Forming Unit:

Pediococcus acidilactici 1.5 billion CFU (6.0%)

Bifidobacterium brevis 0.5 billion CFU (2.0%)

Bifidobacterium infantis 0.5 billion CFU (2.0%)

Lactobacillus paracasei 0.5 billion CFU (2.0%)

Lactobacillus salivarius 0.5 billion CFU (2.0%)

Bifidobacterium lactis 1.0 billion CFU (4.0%)

Bifidobacterium longum 1.0 billion CFU (4.0%)

Streptococcus thermophilus 1.0 billion CFU (4.0%)

Lactobacillus bulgaricus 1.0 billion CFU (4.0%)

Lactobacillus casei 2.5 billion CFU (10.0%)

Lactobacillus plantarum 2.5 billion CFU (10.0%)

Lactobaci! Lus acidophilus 3.0 billion CFU (12.0%)

Bifidobacterium bifidum 3.5 billion CFU (14.0%)

Lactobacillus rhamnosus 6.0 billion CFU (24.0%)

It will be understood that a variety of different mixtures of Lactobacillus, Bifidobacterium, Saccharomyces, Lactococcus, and other probiotic organisms can be combined with Pediococcus in various percentages of compositions and doses that produce effective results; The invention is not limited to the exact formulation described above.

Methods for the formulation and encapsulation of bacteria have been reported, and such methods can be used in conjunction with this invention (eg, US Patent Application 2004/247580).

Additionally, the compositions can be formulated, prepared, or used to include prebiotic agents that promote the growth of probiotic organisms in the gastrointestinal tract. Suitable prebiotic agents include, but are not limited to, fructooligosaccharides, galactooligosaccharides, lactulose, p-glucan, inulin, pectin, and resistant starch (see, eg, Paul et al., US 6,241,983).

The probiotic compositions of the invention are also formulated with other therapeutic agents such as proton pump inhibitors selected from the group consisting of omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole and H2 receptor antagonists selected from the group consisting of Cimetidine, Ranitidine, Famotidine and Nizatidine.

Example 1

A 38-year-old male patient with severe bloating is treated daily with a capsule containing 200 million CFU of Pediococcus acidilactici. The patient is evaluated on a weekly basis and patient information indicates improvement in the symptoms of bloating.

Example 2

An 8-year-old boy with daily gas, abdominal cramps, and constipation is treated by administering 2 capsules twice a day, each capsule containing a probiotic formulation containing Pediococcus acidilactici 1.5 billion colony forming units (CFU), Bifidobacterium brevis 0.5 billion CFU, Bifidobacterium infantis 0.5 billion CFU, Lactobacillus paracasei 0.5 billion CFU, Lactobacil! Us salivarius 0.5 billion CFU, Bifidobacterium lactis 1.0 billion CFU, Bifidobacterium longum 1.0 billion CFU, Streptococcus thermophilus 1.0 billion CFU, Lactobacillus bulgaricus 1.0 billion CFU, Lactobacillus casei 2.5 billion CFU, Lactobacillus plantarum 2.5 billion CFU, Lactobacillus acidophilus 3.0 billion CFU, Bifidobacterium bifidum 3.5 billion CFU, and Lactobacillus rhamnosus 6.0 billion CFU and undergoes full resolution of the symptoms after 3 weeks.

Reference is made to the full contents including the references cited therein from the references cited above and the patents and published applications that follow, including all their equivalents and foreign journal publications.

US patent documents

US Patent Date Inventor

5,705,152 January, 1998 Plummer

5,501,857 March, 1996 Zimmer

6,080,401 June, 2000 Reddy, et al.

6,241,983 June, 2001 Paul et al .

6,251,391 June, 2001 Wilkinson, et al.

7,241,441 July, 2007 Choi, et al.

US patent applications

US Patent Application Publication Date Inventor

2004/0247580 December 9, 2004 Chung et al.

2006/0165661 Jul 27, 2006 Speelmans, et al.

2007/0286916 December 13, 2007 Bengmark

2010/0196323 August 5, 2010 Plail, et al.

2009/0263366 October 22, 2009 Lin

2005/0186188 Aug 25, 2005 Guo

2006/0251633 November 9, 2006 Salvadori, et al.

2006/0008511 January 12, 2006 Lin & Lin

2007/0020328 January 25, 2007 Lin

2010/0278975 November 4, 2010 Chung, et al.

World patent documents

WO2004 / 103083 December 2, 2004 Ljungh-Wadstrom WO2004 / 110466 December 23, 2004 Speelmans G, et al.

WO2010 / 002054. January 7, 2010 Chung Myung Jun et al.

Other references

1. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104 Suppl 1: S1-S35.

2. Blaser MJ. Helicobacters are indigenous to the human stomach: duodenal ulceration is due to changes in gastric microecology in the modem era. Gut 1998; 43: 721-727

3. Bullock NR, Booth JC, Gibson GR. Comparative composition of bacteria in the human intestinal microflora during remission and active ulcerative colitis. Curr Issues Intest Microbiol 2004; 5 (2): 59-64.

4. Camilleri M, Tack JF. Current medical treatments of dyspepsia and irritable bowel syndrome. Gastroenterol Clin North Am 2010; 39 (3): 481-93.

5. Chang JY and Talley NJ. Current and emerging therapies in irritable bowel syndrome: from pathophysiology to treatment. Trends Pharmacol Sci 2010; 31 (7): 326-34.

6. Chermesh I, et al. Failure of Synbiotic 2000 to prevent postoperative recurrence of Crohn's disease. Dig Dis Sci 2007; 52: 385-389.

7. Choi CH, et al. A randomized, Double-blind, placebo-controlled multicenter trial of Saccharomyces boulardii in irritable bowel syndrome: effect on quality of life. J Clin Gastroenterol 2011 Feb 4. [electronic publication before printing]

8. Collins SM, et al. The putative role of the intestinal microbiota in the irritable bowel syndrome. Dig Liver Dis 2009; 41 (12): 850-3.

9. Corthésy B, Gaskins HR, Mercenier A. Cross-talk between probiotic bacteria and the host immune system. J Nutr 2007; 137: 781S-790S.

10. Engel MA, Neurath MF. New pathophysiological insights and modern treatment of IBD. J Gastroenterol 2010; 45 (6): 571-83.

11. FAO / WHO (2002). Guidelines for the evaluation of probiotics in food. London, Ontario, Canada, April 30 and May 1, 2002.

12. Gareau MG, Sherman PM, Walker WA. Probiotics and the gut microbiota in intestinal health and disease. Nat Rev GastroenterolHepatol 2010; 7: 503-514.

13. Grundmann O, Yoon SL, Moshiree B. Current developments for the diagnosis and treatment of irritable bowel syndrome. Curr Pharm Des. 2010; 16 (33): 3668-45.

14. Guslandi M, et al. Saccharomyces boulardii in maintenance treatment of Crohn's disease. Dig Dis Sci 2000; 45: 1462-4.

15. Holzapfel WH, Schillinger U. Introduction to pre and probiotics. Food Res Int 2002; 35: 109-116.

16. Holzapfel WH, et al. Taxonomy and important features of probiotic microorganisms in food and nutrition. Am J Clin Nutr 2001; 73 (2 Suppl): 365S-73S.

17. Ishibashi N, Yamazaki S. Probiotics and safety. Am J Clin Nutr 2001; 73 (2 Suppl): 465S-470S.

18. Jonkers D, Stockbrügger R. Review Article: Probiotics in gastrointestinal and liver diseases. Aliment Pharmacol Ther 2007; 26 (Supplement s2): 133-148.

19. Kang JS, Lee MS. Anti-Helicobacter pylori activity of Pediococcus acidilactici GMB7330 isolated from infant feces. Korean J Microbiol 2005; 41 (2): 152-156.

20. Kim TS, et al. Antagonism of Helicobacter pylori by bacteriocins of lactic acid bacteria. J Food Prot 2003; 66 (1): 3-12.

21. Kruszewska K, et al. Selection of lactic acid bacteria as probiotic strains by in vitro tests. Microecol Ther 2002; 29: 37-51.

22. Lesbros-Pantoflickova D, Corthésy-Theulaz I, Blum AL. Helicobacter pylori and probiotics. J Nutr 2007; 137 (3 Suppl 2): 812S-8S.

23. Lin, HC. Small intestinal bacterial overgrowth - a framework for understanding irritable bowel syndrome. JAMA 2004; 292: 852-858.

24. Loftus EV, Silverstein MD, Sandborn WJ, et al. Ulcerative colitis in Olmsted County, Minnesota, 1940 1993: incidence, prevalence, and survival. Gut 2000; 46: 336-343.

25. Longstreth GF, et al. Functional bowel disorders. Gastroenterology 2006; 130: 1480-149.

26. Madden JAJ, Hunter JO. A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics. Br J Nutr 2002; 88 Suppl 1: S67-S72

27. Midolo PD, et al. In vitro inhibition of Helicobacter pylori NCTC 11637 by organic acids and lactic acid bacteria. J Appl Bacteriol 1995; 79 (4): 475-9.

28. Moayyedi P, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut 2010; 59 (3): 325-32.

29. Ott SJ, et al. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease Gut 2004; 53: 685-693.

30. Parvez S, Malik KA, Ah Kang S, Kim HY. Probiotics and their fermented food products are beneficial for health. J Appl Microbiol 2006; 100: 1171-85.

31. Pimentel M, Lembo T, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011; 364: 22-32.

32. Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol. 2011; 8 (2): 79-88.

33. Salonen A, de Vos WM, and Palva A. Gastrointestinal microbiota in irritable bowel syndrome: present state and perspectives. Microbiology 2010; 156: 3205-3215.

34. Sepulveda AR, Patil M. Practical approach to the pathologic diagnosis of gastritis. Arch Pathol Lab Med.

2008; 132 (10): 1586-93.

35. Silverberg MS, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease. Report of a working party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol 2005; 19 Suppl A: 5A-36A.

36. Simpson WJ, Taguchi H. The genus Pediococcus, with notes on the genera Tetratogenococcus and Aerococcus, In Wood BJB, Holzapfel WH (eds). The Genera of Lactic Acid Bacteria. nineteen ninety five; pp. 125-172; Chapman & Hall, London.

37. Szajewska H, Horvath A, Piwowarczyk A. Meta-analysis: the effects of Saccharomyces boulardii supplementation on Helicobacter pylori eradication rates and side effects during treatment. Aliment Pharmacol Ther 2010; 32 (9): 1069-79.

38. Tannock GW. Identification of lactobacilli and bifidobacteria. Current Issues Molec Biol 1999; 1: 53-64.

39. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 2006; 101: 1581-90.

Although the present invention has been described with reference to specific details of certain embodiments thereof, such details are not intended to be construed as limitations.

Claims (14)

1. A pharmaceutically acceptable composition comprising approximately the following amounts of ingredients per serving or dose, where CFU stands for a Cologne Forming Unit: Pediococcus acidilactici 1.5 billion CFU Bifidobacterium brief 0.5 billion CFU Bifidobacterium infantis 0.5 billion CFU Lactobacillus paracasei 0.5 billion CFU Lactobacillus salivarius 0.5 billion CFU Bifidobacterium lactis 1.0 billion CFU Bifidobacterium longum 1.0 billion CFU Streptococcus thermophilus 1.0 billion CFU Lactobacillus bulgaricus 1.0 billion CFU Lactobacillus casei 2.5 billion CFU Lactobacillus plantarum 2.5 billion CFU Lactobacillus acidophilus 3.0 billion CFU Bifidobacterium bifidum 3.5 billion CFU Lactobacillus rhamnosus 6.0 billion CFU for use in a method of amelioration and treatment of at least one symptom of irritable bowel syndrome, inflammatory bowel disease, or gastritis in a mammal in need. 2. The composition for use of claim 1, wherein the symptom that is improved is selected from the group consisting of: a stabbing or burning pain or ailment in the upper abdomen; nausea; threw up; loss of appetite; belching or bloating; a feeling of fullness in the upper abdomen after eating; weightloss; gastric ulcer; duodenal ulcer; inflammation of the inner lining of the stomach; a positive urease test in the stool; a positive urea breath test; gas (flatulence); diarrhea or constipation; a change in the frequency of bowel movements; a change in the appearance of bowel movements; feelings of uncontrollable urgency to have a bowel movement; mucus in the stool; pain with passing stool; rectal bleeding; bloody stools; intestinal inflammation; intestinal abscesses and / or fistulas; and pouchitis. 3. The composition for use according to claim 1, wherein the composition contains an additional Saccharomyces probiotic microbial organism , more preferably wherein the additional probiotic microbial organism is selected from Saccharomyces boulardii or Saccharomyces cerevisiae. 4. The composition for use according to claim 1, wherein the composition contains an additional probiotic microbial organism selected from the group consisting of: Lactococcus lactis, Leuconostoc lactis, Leuconostoc pseudomesenteroides, Leuconostoc mesenteroides, Streptococcus thermophilus, Bacillus subtilis, Bacillus , Bacillus licheniformis, Bacillus cereus, Enterococcus faecium, Escherichia coli Nessle 1917, Proprionibacterium acidipropionici, Proprionibacterium freudenreichii, Proprionibacterium jensenii and Proprionibacterium thoenii and mixtures thereof. 5. The composition for use according to claims 1, 3 or 4, wherein none of the probiotic microorganisms contained in the composition has been propagated or cultivated in media containing casein or gluten. 6. The composition for use according to claims 1, 3 or 4, wherein the pharmaceutically acceptable composition is labeled as a dietary supplement. 7. The composition for use according to claims 1, 3 or 4, wherein the pharmaceutically acceptable composition is in the form of a dried powder, a tablet, a hard gelatin capsule or a soft gelatin capsule. 8. The composition for use according to claims 1, 3 or 4, wherein the pharmaceutically acceptable composition is provided in a carrier material suitable for human consumption, preferably where the carrier material is selected from the group consisting of: cereal based product, rice cake, soy cake, food bar product, cold formed food bar product, custard, pudding, gelatin, rice milk, soy milk, yogurt, kefir, fruit puree, caramel, candy bar, and applesauce. 9. The composition for use according to claims 1, 3 or 4, wherein the composition further comprises an antibiotic agent and / or an antifungal agent. 10. The composition for use according to claim 9, wherein the antibiotic agent or antifungal agent is selected from the group consisting of: rifaximin, clarithromycin, azithromycin, amoxicillin, ampicillin, ciprofloxacin, vancomycin, metronidazole, nystatin, itraconazole, fluconazole , or a sulfonamide drug and mixtures thereof. 11. The composition for use according to claims 1, 3, 4, 8, or 10, wherein the pharmaceutically acceptable composition further comprises at least one prebiotic agent that promotes the growth of probiotic microorganisms in the gastrointestinal tract, preferably wherein The prebiotic agent comprises at least one of a fructooligosaccharide, galactooligosaccharide, lactulose, betaglucan, inulin, pectin, and resistant starch. 12. The pharmaceutical composition for the use of claim 1 further comprising another beneficial therapeutic agent selected from the group consisting of: proton pump inhibitors (PPI) and H2 receptor antagonists, preferably wherein said pump inhibitors protons are selected from the group consisting of omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole and wherein said H2 receptor antagonists are selected from the group consisting of Cimetidine, Ranitidine, Famotidine and Nizatidine. 13. A method of manufacturing a medicament capable of ameliorating and treating one or more symptoms associated with irritable bowel syndrome, inflammatory bowel disease, or gastritis in a human patient, said method comprising: combining (a) a pharmaceutically effective amount of a composition according to claims 1, 3, 4, 8, 10, or 12, and (b) a pharmaceutically acceptable adjuvant, excipient, buffer or diluent. 14. A kit comprising a package containing: (a) a composition according to any one of claims 1, 3, 4, 8, 10 or 12; and (b) a label comprising instructions for pharmaceutical use of the composition for ameliorating and treating one or more symptoms of irritable bowel syndrome or inflammatory bowel disease or gastritis.